Peter M, Abe C, Agyepong A
… +10 more, Awe A, Buabeng R, Dean M, Fisher J, Henriques S, Leeson-Beevers K, Nelson C, Walters-Lawrence S, Chitty LS, Hill M
Black women in the UK experience disproportionately poor maternal outcomes yet remain underrepresented in research on prenatal screening and diagnostic genetic testing (prenatal testing). We therefore know little about h...Black women in the UK experience disproportionately poor maternal outcomes yet remain underrepresented in research on prenatal screening and diagnostic genetic testing (prenatal testing). We therefore know little about how Black parents feel and what they understand about these tests. Using a cross-sectional online survey, we assessed attitudes towards prenatal tests, knowledge of genetic terms and prenatal tests, and mistrust amongst Black and mixed Black heritage parents in the UK who had been pregnant in the last five years. 110 parents completed the survey (95% female). Screening was valued by most (89%), although only half (50%) reported willingness to undergo invasive diagnostic testing. Preparing for a child with a genetic condition or disability were key motivators for testing, whilst opposition to termination and concerns about miscarriage risk drove refusal. Healthcare professionals (HCPs) were the main source of information when discussing prenatal testing, though mistrust in healthcare systems was high and associated with lower reported uptake of both screening and diagnostic tests. Nearly three-quarters valued speaking to an HCP who shared their ethnic background. Misconceptions about sickle cell were common, with 40% believing it affects only African and Caribbean populations. While most parents recognised the term 'DNA', only 28% understood the term 'genome'. Our findings highlight support for prenatal testing but reveal knowledge gaps and high mistrust that may undermine informed choice. Addressing misconceptions - particularly around sickle cell and available prenatal tests - alongside culturally responsive counselling and community-based education is essential to achieving equitable prenatal care for Black parents.
Germline variants in CTNNA1, encoding αE-catenin, have been implicated in hereditary diffuse gastric cancer (HDGC) and macular dystrophy patterned-2 (MDPT2). However, the functional mechanisms associated specifically wit...Germline variants in CTNNA1, encoding αE-catenin, have been implicated in hereditary diffuse gastric cancer (HDGC) and macular dystrophy patterned-2 (MDPT2). However, the functional mechanisms associated specifically with each molecular variant type underlying these distinct clinical outcomes remain poorly understood. Here, we established a humanized Drosophila melanogaster model conditionally targeting two distinct Drosophila tissues: the eye and the wing. We assessed the functional impact of eight CTNNA1 variants identified in 50 carrier families. We used tissue-specific RNAi and CRISPR/Cas9 to deplete endogenous Drosophila α-catenin (Dα-cat) and expressed either human wild-type (WT) or mutant αE-catenin (Hα-cat). We demonstrate that WT Hα-cat rescued Dα-cat loss, supporting conserved functionality across species. Hα-cat truncating variants failed to rescue epithelial architecture or viability and were associated with increased apoptosis, although one nonsense variant located in the CTNNA1 last exon exhibited milder phenotypes. Interestingly, while most missense variants behaved similarly to WT, p. Asn853Ser, in CTNNA1 last exon, exhibited partial functional loss and did not fully rescue apoptosis caused by Dcat expression loss. These results highlight variant-type and tissue-type specificities. This work provides a humanized Drosophila model for the CTNNA1 gene, which reveals variant-type and locus-specific impacts of CTNNA1 alterations, occurring either in HDGC or MDPT2 families. Our study highlights the value of in vivo functional modeling for clinical variant interpretation and supports improved classification and management strategies for CTNNA1 variant carriers.
Anandam T, Peters S, Lauretta M
… +2 more, Morgan A, Best S
Eur J Hum Genet
· 2026 May · PMID 41748928
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Genetic practices are increasingly recognised as essential components of modern healthcare. Allied health professionals and nurses are ideally placed to initiate discussions about genetic investigations with patients and...Genetic practices are increasingly recognised as essential components of modern healthcare. Allied health professionals and nurses are ideally placed to initiate discussions about genetic investigations with patients and families. However, there are known barriers such as a lack of confidence and knowledge. A key step to addressing these barriers is identifying implementation strategies that support the integration of genetics across healthcare disciplines. We conducted a systematic review to identify empirical and conceptual implementation strategies to support genetic practices among allied health professionals and nurses. We searched CINAHL, Embase, Emcare, Medline, Scopus, and Web of Science for articles published from 2020. Twenty-eight full-text articles were included in the review. Identified implementation strategies were mapped to the Theoretical Domains Framework (TDF) to identify key areas for behaviour change. Empirical strategies, including workshops, online learning, case-based education, and leadership development, demonstrated positive effects on supporting genetic integration into clinical practice. Conceptual strategies identified included: (1) education/learning, (2) professional development, (3) policy, (4) evaluation tools, and (5) educational resources. The TDF domains of Knowledge, Social Influences, and Social/Professional Role and Identity were commonly found, while the TDF domains of Intentions, Reinforcement, Optimism, Emotion and Goals were underrepresented. Findings demonstrate that empirical and conceptual implementation strategies lack evaluation and tend to focus solely on commonly targeted domains. Future research is needed to investigate the feasibility and effectiveness of implementation strategies, explore the underrepresented domains, and support efforts to increase genetic literacy and practices among allied health professionals and nurses.
Ball M, Baker N, Lim SC
… +6 more, Casauria S, Lunke S, Compton AG, Thorburn DR, Christodoulou J, Stark Z
Eur J Hum Genet
· 2026 May · PMID 41748927
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Genomic sequencing has transformed the diagnostic approach for mitochondrial disease, yet integration into standard clinical practice is limited by access and funding. We conducted a post-implementation evaluation of gen...Genomic sequencing has transformed the diagnostic approach for mitochondrial disease, yet integration into standard clinical practice is limited by access and funding. We conducted a post-implementation evaluation of genome sequencing (GS) for mitochondrial disease in Australia, which became publicly funded through the Medicare Benefits Scheme (MBS) in November 2023, to allow for broader access to testing. Test request data, including demographics, phenotypic information, and the diagnostic outcomes, were collected from November 2023 to May 2025 from the Victorian Clinical Genetics Services, the current laboratory provider of the MBS-funded service. Test uptake was 26% of predicted, with lower test rates in regional and remote areas. Over the first 19 months, 300 individuals suspected of mitochondrial disease underwent GS with a median turnaround time of 84 days (8 days-218 days). The diagnostic yield was 20%, with 56% of diagnoses in known mitochondrial disease genes. Of these, 70% (24 of 34) were in mitochondrial DNA. Seventeen diagnoses were in individuals who had prior non-diagnostic testing (exome sequencing or gene panel). We demonstrate that publicly-funded GS can deliver meaningful diagnostic outcomes for mitochondrial disease on a national scale. To maximise its impact, attention must now shift towards ensuring equitable access, particularly for regional and remote areas, and embedding sustainable mainstreaming models that support both genetic and non-genetic clinicians.
Mehta SG, Holden S, Babar J
… +8 more, Karia S, Wetscherek MTA, Barker AP, White J, Lee SL, Foster A, Maher ER, Marciniak SJ
Eur J Hum Genet
· 2026 May · PMID 41741684
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Spontaneous pneumothorax is a common respiratory presentation that may signal underlying genetic disease. Familial pneumothorax occurs in ~10% of primary cases, yet 75% remain genetically unclassified. We report identica...Spontaneous pneumothorax is a common respiratory presentation that may signal underlying genetic disease. Familial pneumothorax occurs in ~10% of primary cases, yet 75% remain genetically unclassified. We report identical twin brothers presenting with spontaneous pneumothoraces in adulthood, leading to a diagnosis of Tatton-Brown-Rahman syndrome (TBRS), a DNMT3A-related overgrowth disorder not previously associated with pneumothorax. Both individuals exhibited tall stature, mild intellectual disability, hypermobility, and cardiac abnormalities. Whole genome sequencing identified a rare de novo DNMT3A missense variant (c.1585 G > A, p.D529N) absent from population databases and predicted to be damaging. Methylation profiling confirmed genome-wide hypomethylation consistent with impaired DNMT3A function, supporting pathogenicity. No variants were found in known familial pneumothorax genes. Apical blebs observed at surgery and connective tissue features suggest a mechanistic link between TBRS and pneumothorax, analogous to other monogenic connective tissue disorders. This case expands the phenotypic spectrum of TBRS and highlights the importance of genetic evaluation in familial pneumothorax. Diagnosis enables personalised care, including surveillance for extrapulmonary complications such as aortic root dilatation and haematological malignancy. Our findings suggest that TBRS should be considered in patients presenting with pneumothorax, tall stature, and neurodevelopmental features. Further cases are needed to confirm this association and refine clinical management strategies.
Genomic information collected in research settings is a valuable resource that can be shared for future (secondary) research with the consent of the individual. Whether individuals participating in genomic research are c...Genomic information collected in research settings is a valuable resource that can be shared for future (secondary) research with the consent of the individual. Whether individuals participating in genomic research are comfortable with broad consent and all research sharing scenarios is largely unknown. The Australian Reproductive Genetic Carrier Screening Project (Mackenzie's Mission) investigated the feasibility and acceptability of population reproductive carrier screening for severe recessive genetic conditions occurring in childhood. Enrolment and consent for participation was completed digitally using an online Portal or REDCap. Consent included an option to complete ten specific questions about preferences for future research use of samples and data. Preferences for future research were completed by 23.5% (4288) of individuals. The remaining 76.5% gave broad consent to data sharing. Those who chose to complete the questions shared similar demographics to the rest of the cohort. Individuals were most permissive of sharing with not-for-profit (78.0%) and university (78.2%) research organisations, for general (79.8%) and health / medical / biomedical research (82.2%). People were less likely to consent for use by governments (59.2%) and commercial organisations (33.7%). Nearly 60% of people want to be notified every time their data is shared. Updates to consent preferences were made 1785 times, by 282 people. This study supports the need for research programmes to facilitate flexible models of consent, including specific and dynamic consent. It also demonstrates a scalable model in which participant-led choices contribute to reduced ambiguity about data sharing permissions.
Reese JT, Chimirri L, Bridges Y
… +18 more, Danis D, Caufield JH, Gargano MA, Kroll C, Schmeder A, Liu F, Wissink K, McMurry JA, Graefe ASL, Niyonkuru E, Korn DR, Casiraghi E, Valentini G, Jacobsen JOB, Haendel M, Smedley D, Mungall CJ, Robinson PN
Eur J Hum Genet
· 2026 Apr · PMID 41735669
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Large language models (LLMs) show promise in supporting differential diagnosis, but their performance is challenging to evaluate due to the unstructured nature of their responses, and their accuracy compared to existing...Large language models (LLMs) show promise in supporting differential diagnosis, but their performance is challenging to evaluate due to the unstructured nature of their responses, and their accuracy compared to existing diagnostic tools is not well characterized. To assess the current capabilities of LLMs to diagnose genetic diseases, we benchmarked these models on 5213 previously published case reports using the Phenopacket Schema, the Human Phenotype Ontology and Mondo disease ontology. Prompts generated from each phenopacket were sent to seven LLMs, including four generalist models and three LLMs specialized for medical applications. The same phenopackets were used as input to a widely used diagnostic tool, Exomiser, in phenotype-only mode. The best LLM ranked the correct diagnosis first in 23.6% of cases, whereas Exomiser did so in 35.5% of cases. While the performance of LLMs for supporting differential diagnosis has been improving, it has not reached the level of commonly used traditional bioinformatics tools. Future research is needed to determine the best approach to incorporate LLMs into diagnostic pipelines.
Genomic newborn screening (gNBS) provides the potential to offer significant health benefits. However, more evidence, including psychosocial impacts on parents, is needed before gNBS is ready for population-level impleme...Genomic newborn screening (gNBS) provides the potential to offer significant health benefits. However, more evidence, including psychosocial impacts on parents, is needed before gNBS is ready for population-level implementation. The aim of this qualitative study was to explore parental experiences of receiving gNBS results from a prospective study, BabyScreen+. BabyScreen+ screened 1000 newborns for >600 genetic conditions that were early-onset, severe, and had management options available (prevention, surveillance or treatment). We interviewed parents three months after receiving their result. Interviews were analysed using reflexive thematic analysis, guided by Interpretive Description. Twenty-seven parents were interviewed, including nine who received a 'high chance' result for their newborn. Waiting for gNBS results was not unduly anxiety provoking. Low chance results provided psychosocial benefits including peace-of-mind and empowerment. Receiving a high chance result was unexpected and shocking, especially if the result was for a condition with significant treatment recommendations (e.g., transplantation). Psychosocial adaption to the subsequent diagnosis was an evolving process; access to genetic counselling, high-quality information and prompt referrals to specialists increased confidence in managing the condition and facilitated adaptation. All parents valued the high chance gNBS result given its clinical utility. The study provides support for gNBS by highlighting that it can provide valuable health information with minimal harms. Findings can be used to inform the implementation of population-scale gNBS.
Whole genome sequencing (WGS) has generated interest as a potential way to enhance and expand the scope of newborn screening (NBS) programs. The effective implementation of WGS in NBS programs relies on several factors,...Whole genome sequencing (WGS) has generated interest as a potential way to enhance and expand the scope of newborn screening (NBS) programs. The effective implementation of WGS in NBS programs relies on several factors, including parental perceptions. Young adults are potential future parents when WGS is expected to be fully implemented in NBS programs. Therefore, it is essential to understand their perspectives regarding the integration of WGS into NBS programs. Given that there is a dearth of studies in this topic, we explored the perceptions of young adults about the integration of WGS into NBS programs. We conducted semi-structured qualitative interviews with 58 young adults and used the content analysis to analyze the qualitative data. Our findings provide evidence that the majority of our study participants would choose to have their future newborns undergo WGS in NBS programs. The primary motivation for wanting to do so was that WGS would help them to seek out and take measures to prevent diseases for their children. However, some participants expressed concerns about receiving non-medically actionable WGS results. Our findings highlight the need for policymakers, healthcare providers, and researchers to carefully evaluate the type of WGS results returned to parents before integrating WGS into NBS programs.
Hansen J, Strnadová I, Danker J
… +7 more, Jackaman KM, Loblinzk Refalo Oam J, Sarfaraz S, Leach Scully J, Boyle J, Terrill B, Palmer EE
Eur J Hum Genet
· 2026 Apr · PMID 41731182
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People with intellectual disability want to learn more about their health and genetics. They want to be empowered with the knowledge and skills to make informed health and genetic healthcare choices. Little is known abou...People with intellectual disability want to learn more about their health and genetics. They want to be empowered with the knowledge and skills to make informed health and genetic healthcare choices. Little is known about what high school students with intellectual disability learn about health, genetics or genetic healthcare. To address this gap, we conducted an inclusive qualitative research study in Australia. Fourteen Australian current and recently graduated students with intellectual disability participated in semi-structured interviews. Inductive content analysis revealed four key themes: (i) Science, health and genetics education, (ii) Health rights, (iii) Education rights, (iv) Recommendations for improving genetic and health literacy. Students with intellectual disability reported they were not taught about genetics and health, making healthcare choices, and/or making life decisions at school. They felt these disadvantages and were disempowered in becoming informed healthcare consumers. They recommended that teachers should be supported with resources to deliver inclusive, person-centred and respectful lessons that inform decision-making about genetics, health and healthcare choices. Future research should focus on how best to upskill teachers to support students with intellectual disability for their future health choices in a respectful, supportive, student-centred and strengths-based way. This will help prepare young people with intellectual disability to navigate the healthcare system and be empowered partners in their own healthcare. The growth of such skills has been suggested as critical in inequities in healthcare access for people with intellectual disability, as well as improving healthcare experiences and outcomes.
Paivandy A, Lenner F, Eisfeldt J
… +5 more, Jonson T, Ehrencrona H, Lindstrand A, Scherer SW, Feuk L
Eur J Hum Genet
· 2026 May · PMID 41731181
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Identification of genomic rearrangements by microarrays or short-read sequencing frequently lacks information about the exact architecture and breakpoints of variants due to technical limitations. Independent verificatio...Identification of genomic rearrangements by microarrays or short-read sequencing frequently lacks information about the exact architecture and breakpoints of variants due to technical limitations. Independent verification of complex structural variants (SVs) is often performed using custom targeted assays, making confirmation of clinically relevant findings time consuming and laborious. In this study we evaluate Oxford Nanopore long-read adaptive sampling for flexible and rapid confirmation and characterization of complex genomic rearrangements and structural variants. Adaptive sampling is an in silico target enrichment, where continued sequencing or ejection of a fragment is based on whether it matches a defined reference sequence. Using adaptive sampling, we targeted 10 regions with different structural variant types, including deletions, translocations, and complex rearrangements. Each sample was analyzed on a MinION or PromethION flow-cell, and sequencing resulted in between 14.1-18.3 Gb of data per sample, with mean autosomal on-target coverage of 28.4x and off-target read depth coverage of 5.3x. We were able to verify all 10 rearrangements, with breakpoint spanning reads for nine of the ten regions, and fully resolved the architecture of nine regions. We also show that background reads can be used to detect structural variants in non-targeted regions of the genome. Our results show that adaptive sampling represents a flexible and rapid strategy for confirmation and characterization of clinically relevant genomic rearrangements in clinical samples. By providing sequence information, read depth, and methylation data, nanopore adaptive sampling has advantages over other assays for variant confirmation used in diagnostic laboratories today.
A subset of cancers arises due to inherited germline pathogenic variants in specific genes, known as hereditary cancers. These genes typically include tumor suppressors, DNA repair and replication fidelity genes, and occ...A subset of cancers arises due to inherited germline pathogenic variants in specific genes, known as hereditary cancers. These genes typically include tumor suppressors, DNA repair and replication fidelity genes, and occasionally oncogenes. In most hereditary cancer syndromes, Knudson's two-hit hypothesis applies, where a second somatic event inactivates the remaining allele of a tumor suppressor or DNA repair gene, leading to tumorigenesis. Advancements in genome-wide sequencing have significantly enhanced our understanding of the mutational processes involved in hereditary cancers. In particular, the assessment of microsatellite instability (MSI), tumor mutational burden (TMB), and mutational signatures has emerged as a powerful tool for the identification of hereditary tumors. Tumors with high or ultra-high TMB often reflect underlying DNA repair deficiencies, while specific mutational signatures can pinpoint the defective pathway. These tumor mutational features are especially informative in syndromes involving mismatch repair (MMR), homologous recombination (HR), base excision repair (BER), nucleotide excision repair (NER), and polymerase proofreading. Moreover, tumor sequencing aids in the interpretation of germline variants, identifies somatic mosaicism, and helps differentiate hereditary from sporadic cancers. Additionally, tumor molecular features associated with DNA repair deficiencies offer insights into personalized therapies, such as the use of PARP inhibitors for BRCA1/2-deficient tumors and immune checkpoint inhibitors for MMR- and polymerase proofreading-deficient cancers. Tumor profiling also uncovers actionable mutations in oncogenes like RET and VHL, which can be targeted with specific therapies. This review explores the integration of tumor molecular features with germline genetic data to refine diagnosis, risk assessment, and therapeutic strategies in hereditary cancer.
The Personal Utility Scale (PrU) was developed in the United States to measure the usefulness of genomic results across self-knowledge, reproductive planning and practical benefits. We aimed to evaluate and validate the...The Personal Utility Scale (PrU) was developed in the United States to measure the usefulness of genomic results across self-knowledge, reproductive planning and practical benefits. We aimed to evaluate and validate the model with data from an Australian context. Participants (N = 1526) from a population-based genomic screening study (DNA Screen) completed a survey including the PrU at two time points following receipt of genomic results. We used confirmatory factor analysis (CFA) to assess model fit and evaluated reliability and validity through internal consistency (Cronbach's alpha) and correlations with related and distinct constructs. A three-factor oblique CFA model demonstrated acceptable fit of our previously reported factor structure (RMSEA = 0.09; CFI = 0.93; TLI = 0.92), with factor loadings ranging from 0.66-0.84 (self-knowledge), 0.68-0.84 (practical benefits), and 0.81-0.87 (reproductive planning). Internal consistency was high (Cronbach's α = 0.92; CI: 0.91-0.93). The FACToR positive feelings subscale was negatively correlated with the PrU overall score (r = -0.45, p < 0.001), consistent with theoretical expectations. Minimal correlation with K10 scores (r = -0.06, p = 0.07) supported discriminant validity. Our personal utility model demonstrated strong performance in an Australian sample. We validated the proposed three-factor structure, indicating the model reliably captures distinct dimensions of personal utility. As genomics becomes integrated into population screening, understanding how individuals value and use their results is essential. Our findings support the use of the PrU scale in the United States and Australia, contributing to ongoing efforts to evaluate the impact of genomic information in population screening programs and suggesting promise for use in other countries.
Durmaz CD, Güleray Lafcı N, Erkan DD
… +7 more, Akçin ÖÇ, Bulut N, Kuş F, Ateş Özdemir D, Neesen J, Dremsek P, Dizdar Ö
Eur J Hum Genet
· 2026 Mar · PMID 41708839
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Hereditary epidermodysplasia verruciformis (EV) represents a paradigmatic inherited cutaneous syndrome linking viral susceptibility, immunity, and oncogenesis. Although biallelic variants in CIB1, TMC6, and TMC8-encoding...Hereditary epidermodysplasia verruciformis (EV) represents a paradigmatic inherited cutaneous syndrome linking viral susceptibility, immunity, and oncogenesis. Although biallelic variants in CIB1, TMC6, and TMC8-encoding components of the keratinocyte-intrinsic antiviral complex-underlie most cases, the full mutational spectrum and its oncologic implications remain incompletely defined. We performed integrated genomic, histopathological, and longitudinal clinical analyses in six affected individuals from five unrelated families with confirmed hereditary EV. Comprehensive short-read sequencing, copy-number assessment, and optical genome mapping (OGM) were used to delineate the underlying genetic alterations, followed by long-range PCR and Sanger validation. Pathogenic or likely pathogenic germline variants affecting TMC6 or TMC8 were identified in all probands, providing molecular confirmation of disease. Four variants were novel, including splice-site, frameshift, and in-frame deletions. In one proband, OGM revealed a previously unrecognised complex del-inv-del structural variant spanning both TMC6 and TMC8-the first reported example in hereditary EV. This rearrangement, confirmed at base-pair resolution, co-segregated with a synonymous TMC8 variant that served as a practical haplotypic marker for carrier testing. Clinically, all patients developed cutaneous squamous cell carcinoma (SCC), and several exhibited multifocal or aggressive disease, underscoring the deterministic malignant potential of hereditary EV. This study broadens the genetic and phenotypic spectrum of TMC6/TMC8-associated EV, establishes complex structural rearrangement in the molecular etiology, and consolidates hereditary EV as a recessive cancer predisposition syndrome. Integrating high-resolution genome mapping into diagnostic workflows may uncover concealed allelic architecture in unresolved hereditary cancer syndromes.
Polycystic kidney disease (PKD) is a Mendelian renal disease characterised by the development of cysts and progressive decline in kidney function, leading to kidney failure. Although genetic testing can provide a precise...Polycystic kidney disease (PKD) is a Mendelian renal disease characterised by the development of cysts and progressive decline in kidney function, leading to kidney failure. Although genetic testing can provide a precise molecular diagnosis of PKD in the majority of cases, 6-13% of patients remain unsolved. Copy number variants (CNVs) are an established pathogenic mechanism in PKD, however detection typically relies on multiplex ligation-dependent probe amplification (MLPA) which is resource intensive and separate to next-generation sequencing (NGS) pipelines. Here, a bioinformatics tool ClinCNV was used to call CNVs from NGS data of 371 people with PKD who had previously undergone short nucleotide variant (SNV) analysis with a standard NGS pipeline. Diagnostic CNVs were confirmed in 13 patients across 7 families, increasing the diagnostic yield from 86.5 to 90.0%. We also tested CNVs as potential disease modifiers. Regression models indicated an association of cystic gene duplication burden to worse kidney survival (HR = 1.56, 95% CI: 1.26, 1.93, adj-p = 0.0004). These models also revealed that duplication burden in genes unrelated to cystic kidney disease associated with the absence of liver cysts, possibly driven by a region containing LRP5L. These results demonstrate the utility of targeted gene panel and exome sequencing for the detection of CNVs in key PKD genes.
Simon AJ, Neustadter-Blackman M, Lev A
… +12 more, Nayshool O, Kellerman R, Glaser F, Levy S, Smoom R, Barel O, Mandola A, Regev M, Naor S, Adam E, Tzfati Y, Somech R
Eur J Hum Genet
· 2026 May · PMID 41703052
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Telomere biology disorders (TBDs) are characterized by bone marrow failure (BMF) and dysfunctional telomeres. So far, inherited mutations in 18 genes have been identified in TBDs. Here, we describe a child presenting wit...Telomere biology disorders (TBDs) are characterized by bone marrow failure (BMF) and dysfunctional telomeres. So far, inherited mutations in 18 genes have been identified in TBDs. Here, we describe a child presenting with early BMF, immunodeficiency, and severely short and defective telomeres, carrying a homozygous splicing mutation (c.409-2 A > G; p.Q136_K138del) in RPA2 - a known replication factor and telomerase accessory factor. The Q136_K138del mutation is predicted to compromise the binding of RPA2 to the single-stranded telomeric DNA. Sequencing of single telomeres revealed that telomere variant repeats (TVRs), present also in healthy individuals, became more prominent in the short telomeres of the patient. Such TVRs may aggravate the telomere dysfunction due to lower affinity to the shelterin proteins. The severe telomere shortening and the activation of DNA damage response at telomeres indicate that this RPA2 mutation causes TBD in a similar manner to other known mutations and should be considered in patients displaying clinical TBD features.
In the context of limited resources and growing demand, patients access genetic testing for hereditary breast and ovarian cancer (HBOC) through various service models, some of which include genetic counseling sessions. T...In the context of limited resources and growing demand, patients access genetic testing for hereditary breast and ovarian cancer (HBOC) through various service models, some of which include genetic counseling sessions. This study assessed the impact of these service models and participation in genetic counseling on patients' experiences and satisfaction with the genetic testing process. A total of 501 patients undergoing genetic testing for HBOC completed a 35-item survey, which included the Genetic Counseling Satisfaction Scale, the Decision Regret Scale, and a modified Royal Marsden Satisfaction Questionnaire. Additional information was gathered from the medical records. Descriptive statistics and Fisher's exact tests were employed for the analysis. Four aspects of the genetic testing experience differed between service models and attendance to genetic counseling: i) receipt of informational materials prior to testing, ii) information that additional discussions with the genetic team were possible, iii) clarity regarding the timeline for receiving results, and iv) explanation of how the results would be delivered. The service model and participation in genetic counseling seem to influence patients' experiences with genetic testing for HBOC. However, satisfaction was generally high and decision regret was low across all service models, highlighting the promise of care models designed to enhance accessibility.
McCrary JM, Van Valckenborgh E, Horgan D
… +69 more, Aleksandrova E, Bargou R, Behulova RL, Belina I, Bøhme ALE, Brunet J, Burada F, Chirita-Emandi A, Ciuca A, Colas C, Constantinidou A, Curca RO, Cursaru V, Dalmas M, Daneberga Z, de Azambuja E, De Pauw A, De Putter R, Delikurt-Tuncalp T, Donnelly D, Ehrencrona H, Foretova L, Galli F, Genuardi M, Giles R, Grima C, Janavičius R, Kääriäinen H, Klink B, Krajc M, Kufel-Grabowska J, Lace B, Leitsalu L, Le Tourneau C, Lodahl M, Mari F, Matos E, Mazzarella L, Milagre TH, Mistrik M, Moss B, Nolan A, O'Shea R, Paneque M, Patócs A, Pestoff R, Poirel HA, Risch M, Rodrigues M, Roetzer KM, Ros A, Schröck E, Schwaninger G, Slámová L, Stamatopoulos K, Strang-Karlsson S, Szczałuba K, Szymczak V, Theis P, Turner J, Valcina O, Vella C, van Zelst-Stams WAG, Wadt KAW, Zschocke J, Ronez J, Ripperger T, Van Den Bulcke M, Bergmann AK
Eur J Hum Genet
· 2026 May · PMID 41688774
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Europe's Beating Cancer Plan is a substantial European Union (EU) investment into cancer prevention and treatment. Integration of genetic services towards personalised cancer prevention and care is a flagship of this pla...Europe's Beating Cancer Plan is a substantial European Union (EU) investment into cancer prevention and treatment. Integration of genetic services towards personalised cancer prevention and care is a flagship of this plan. Genetic counselling is critical to this integration, facilitating informed patient decision making and improved clinical management. However, growing demands for genetic testing and concurrently increasing workforce shortages necessitate new strategies to equitably ensure sustainable access to counselling across the EU. This project aimed to inform future European activities by identifying priority European strategies for addressing common European genetic literacy, workforce, and reimbursement barriers to genetic counselling in cancer noted in prior work. A Delphi survey was conducted, with genetics, oncology, and patient stakeholders invited from all EU Member States. The response rate was 62% (124 total invitations). Over three phases, 77 participants - 28 geneticists; 14 oncologists; 18 genetic counsellors; 16 patient representatives; 1 otherwise qualified expert - rated 19 strategies according to their Importance, Urgency, and Feasibility and selected their top three priority strategies. Five strategies met pre-defined consensus thresholds and received a clear plurality of priority ratings: (1) EU-wide genetic counsellor recognition; (2) Including genetics expertise in oncology guideline creation; (3) Shared EU genetic counsellor registration/education with legal weight; (4) Mandatory counselling reimbursement when clinical guidelines are met; (5) Mandatory inclusion of genetics in oncology fellowship/continuing education. Results provide a roadmap of European actions which promise to sustainably improve access to genetic counselling in cancer care. Upcoming and ongoing EU projects promise to advance their implementation.
Mighton C, Jan A, Lee L
… +7 more, Bouffler S, Downie L, Clausen M, Gaff C, Bombard Y, Stark Z, Martyn M
Eur J Hum Genet
· 2026 May · PMID 41688773
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Digital tools for pre-test education provision and decision support could assist the scalability of opportunistic genomic screening. We evaluated the utility of a digital platform, the Genetics Adviser (GA), for supporti...Digital tools for pre-test education provision and decision support could assist the scalability of opportunistic genomic screening. We evaluated the utility of a digital platform, the Genetics Adviser (GA), for supporting parental decisions about screening for additional findings in the paediatric acute care context. Parents of children who had completed ultrarapid diagnostic genomic testing in the acute setting were offered opportunistic screening following hospital discharge. Interested participants were provided with optional access to GA and offered pre-test genetic counselling (GC). GC sessions were audio-recorded, transcribed verbatim, and participant/counsellor interactions qualitatively analysed to examine the impact of GA use on counselling sessions. Surveys were administered: prior to and after pre-test GC; 1 month after return of results. One hundred and sixty-seven families were offered genomic screening and given access to GA. Family engagement with GA was 52% (87/167) overall, with three-quarters (81/119) of those who attended genetic counselling having engaged with GA. GA use impacted genetic counselling: in consultations where not all parents used GA, more concerns were raised and more questions asked about topics included in GA; GCs also spent more time clarifying values or understanding. GA users correctly answered more knowledge questions at every survey time point. Eighty-three per cent of post-result survey respondents believed GA contained enough information for them to make decisions about opportunistic screening without additional genetic counselling. These findings demonstrate the utility of GA in supporting the scalability of opportunistic genomic screening.